DRUGS IN PIPELINE Pr JC YOMBI UCL-AIDS REFERENCE CENTRE BREACH Sept 27, 2015
N(t)RTI
The Development of TAF TAF Delivers the High Potency of TDF While Minimizing Off- Target Kidney and Bone Side Effects GI TRACT PLASMA RENAL TUBULAR CELL TDF (tenofovir disoproxil fumarate) 300 mg TAF (tenofovir alafenamide) 25 mg 91% lower plasma TFV RENAL TUBULAR CELL TFV TFV LYMPHOCYTE HIV 1. Lee W et. Antimicr Agents Chemo 2005;49(5):1898-1906. 2. Birkus G et al. Antimicr Agents Chemo 2007;51(2):543-550. 3. Babusis D, et al. Mol Pharm 2013;10(2):459-66. 4. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449-5. 5. Sax P, et al. JAIDS 2014. 2014 Sep 1;67(1):52-8. 6. Sax P, et al. Lancet 2015. Jun 27;385(9987):2606-15
FTC/TAF
TAF combinations EVG/COBI/FTC/TAF (Genvoya ): FTC/TAF and RPV/FTC/TAF: TAF treatment HBV infection : Phase III DRV/COBI/FTC/TAF: Johnson&Johnson EMA: European Medicines Agency approval
DARU/COBI/FTC/TAF AMBRE: Double BLIND 1:1 Daru/cobi/TAF/FTC VS Daru/cobi/TDF/FTC NAÏF, CV 1000 copies CD4>50 GFR 50ml/min EMERALD: Open label 2:1 -Daru/cobi/TAF/FTC VS PI/r TDF/FTC Indetectable, CV<50copies, GFR 50ml/min sous PI/r TDF/FTC
TAF Program Expected Approvals and EU Europe E/C/F/TAF 5 th Nov 2015 23th Nov 2015 F/TAF Q2-2016 R/F/TAF Q2/3-2016 D/C/F/TAF (Johnson & Johnson) 2017 2018 TAF single agent (for HBV) 2017 15
NNRTI
DORAVIRINE
P007: DOR + TDF/FTC vs EFV + TDF/FTC in ART-Naive Pts Infected With HIV Double-blind, randomized, 2-part study Pts were stratified by HIV-1 RNA or > 100,000 copies/ml Wk 96 ART-naive, HIV-positive pts with HIV-1 RNA 1000 copies/ml and CD4+ cell count 100 cells/mm 3 (N = 216*) Doravirine + TDF/FTC (n = 108) Efavirenz + TDF/FTC* (n = 108) *Combined pts from 2 study parts: Part 1 was a dose-finding study (n = 84) and Part 2 enrolled additional pts with the current dosing schema (n = 132). Doravirine dosed at 100 mg QD. Efavirenz dosed at 600 mg QD. Wk 24 results reported. Gatell JM, et al. IAS 2015. Abstract TUAB0104.
P007: Key Results Pts With HIV-1 RNA < 40 c/ml, %* DOR + TDF/FTC (n = 108) EFV + TDF/FTC (n = 108) Wk 8 27.8 26.9 Wk 16 63.6 57.5 Wk 24 72.2 73.1 Baseline HIV-1 RNA 83.3 100,000 c/ml (n/n) (55/66) Baseline HIV-1 RNA 60.5 > 100,000 c/ml (n/n) (23/38) 85.7 (54/63) 65.8 (25/38) Event, % DOR + TDF/FTC (N = 108) *NC = F approach. Observed failure approach. Most virologic failure was due to low-level viremia Virologic failure, HIV-1 RNA 40 copies/ml: DOR, 15.7%; EFV, 10.2% Virologic failure, HIV-1 RNA 200 copies/ml: DOR, 3.7%; EFV, 0.9% Resistance testing was performed in 1 pt in each arm who failed treatment; no NRTI or NNRTI mutations detected EFV + TDF/FTC (N = 108) One or more AE 75.9 84.3 Serious AE 0.9 4.6 Discontinued due to AE 0.9 5.6 Drug-related AE 27.8 55.6 Pts with 1 CNS event 26.9 46.3 Gatell JM, et al. IAS 2015. Abstract TUAB0104.
DORAVIRINE MERCK 021: Placebo Dble blind Ratio 1:1 Dorarivine: MK1439 100mg + Lamivudine 300mg + TDF 300mg OU Atripla Naïfs CV 1000 GFR 50ml/min MERCK 024: Open Label 2:1 Doravirine OU PI/r - 2 NRTI CV<40copies since 6 months and 2X GFR 50ml/min First or second treatment PI/r- NRTI (2)
INHIBITORS OF MATURATION
HIV-1 Life Cycle Maturation Fusion Release gp120 Assembly/ cleavage Attachment CD4 Viral DNA Chemokine co-receptor Reverse transcription Human genomic DNA Accessory viral proteins Translation Gag Pol Gag Budding Integration (strand transfer) Transcription Lataillade et al. CROI 2015, Abstract 114LB.
Maturation Inhibitors (MIs): BMS-955176 Mode of Action Mature virus Maturation Protease Untreated Treated with BMS-955176 Immature virus BMS-955176 Gag polyprotein Protease Maturation inhibitor BMS-955176 inhibits the last protease cleavage event between capsid (CA) protein p24 and spacer peptide 1 (SP1) in Gag, resulting in the release of immature, non-infectious virions Adamson et al. Expert Opin Ther Targets 2009; 13:895 908; Sundquist et al. Cold Spring Harb Perspect Med 2012; 2:7. Lataillade et al. CROI 2015, Abstract 114LB.
BMS-955176: Profile of a Second Generation MI BMS-955176 is a second-generation MI that binds reversibly and with greater affinity to HIV-1 Gag than a first-generation MI (bevirimat; BVM) 1,2 Potent in vitro activity towards HIV-1, even in the presence of naturally occurring Gag polymorphisms associated with reduced BVM susceptibility 2 In vitro activity against PI-, NRTI-, NNRTI-, and INSTI-resistant isolates 2 In a 10-day BMS-955176 monotherapy proof-of-concept study: Maximum median declines in HIV-1 RNA of >1 log 10 c/ml (at doses 20 120 mg QD) were achieved that plateaued at ~1.64 log 10 c/ml at doses between 40 mg and 120 mg QD 3 Similar antiviral activity toward both wild-type HIV-1 and HIV-1 with Gag polymorphisms not responsive to BVM 3 BMS-955176 was generally well tolerated 3 Two drug combination studies in vitro demonstrated that BMS-955176 + ATV had an additive effect. Due to the proximity of their sites of inhibition in the virus life cycle and the potential for synergy, we assessed the antiviral activity and safety of BMS-955176 with ATV±RTV 1. Lin et al. CROI 2015; Abstract 42; 2. Nowicka-Sans et al. IAS 2015; Poster TUPEA078; 3. Lataillade et al. CROI 2015; Abstract 114LB. ATV, atazanavir; INSTI, integrase strand transfer inhibitors; PI, protease inhibitor; RTV, ritonavir
AI468002: Part B Study Design* TDF/FTC 300/200 mg + ATV 300 mg + RTV 100 mg BMS-955176 40 mg + ATV 300 mg + RTV 100 mg BMS-955176 40 mg + ATV 400 mg BMS-955176 80 mg + ATV 400 mg Days 1 28 Dosing period Day 30 Furloughed Days 35 Outpatient visits Day 42 Discharge Inpatient days: Day -1 to Day 30 Objectives: Change in plasma HIV-1 RNA levels from baseline to Day 28 Safety and tolerability of BMS-955176 during combination therapy Key inclusion criteria: HIV-1 subtype B-infected subjects Treatment-naïve (<1 week of antiretroviral treatment) or - experienced (PI and MI naïve) subjects Plasma HIV-1 RNA 5,000 c/ml CD4+ T-cell count 200 cells/µl * For all dose groups: BMS-955176 (n=8) and standard of care (n=4). Standard-of-care control arm. TDF/FTC given as a fixed-dose combination. or per investigator s discretion. All doses were QD. ATV, atazanavir; FTC, emtricitabine; MI, maturation inhibitor; PI, protease inhibitor; RTV, ritonavir; TDF, tenofovir disoproxil fumarate.
Conclusions BMS-955176 is a potent, once-daily, second-generation MI BMS-955176 80 mg + ATV and BMS-955176 40 mg + ATV + RTV demonstrated similar antiviral activity (~2.2 log 10 c/ml median decline) compared to the standard of care control over the 28-day treatment period BMS-955176 was generally well tolerated There were no SAEs or AEs leading to discontinuation BMS-955176 + unboosted ATV was associated with lower median changes from baseline in bilirubin levels compared to the arms with boosted ATV A Phase IIb study investigating BMS-955176 + ATV in a booster-sparing and nucleot(s)ide-sparing regimen in treatment-experienced patients initiated July 2015
ATTACHMENT INHIBITOR
AI438011: Efficacy of Fostemsavir + RAL + TDF in Treatment-Experienced Pts Randomized, active-controlled, phase IIb study, blinded to dose Fostemsavir (BMS-663068): HIV-1 attachment inhibitor prodrug, metabolized to temsavir attachment inhibitor; proposed MOA is by binding gp120 to prevent viral attachment and host CD4+ cell entry; active against R5, X4, and dual tropic HIV-1 Wk 24: 1 endpoint Wk 48 HIV-infected pts with exposure to 1 ARV for 1 wk, HIV-1 RNA 1000 c/ml, CD4+ 50 cells/mm 3, virus susceptible to RAL, TDF, ATV, and temsavir IC 50 < 100 nm (N = 251) Feinberg J, et al. IDWeek 2015. Abstract 1075. Fostemsavir 400 mg BID + RAL + TDF (n = 50) Fostemsavir 800 mg BID + RAL + TDF (n = 49) Fostemsavir 600 mg QD + RAL + TDF (n = 51) Fostemsavir 1200 mg QD + RAL + TDF (n = 50) ATV/RTV 300/100 mg QD + RAL + TDF (n = 51) Wk 96
HIV-1 RNA < 50 c/ml, % (95% CI) AI438011 : Virologic Suppression With Fostemsavir + RAL + TDF at Wk 48 100 80 60 40 20 Wk 48 HIV-1 RNA < 50 c/ml (%) 400 mg BID 91 800 mg BID 73 600 mg QD 69 1200 mg QD 79 ATV/RTV 88 0 0 4 8 12 16 20 24 32 40 48 No significant differences in virologic efficacy through Wk 48 regardless of race, sex, age, baseline HIV-1 RNA, or baseline CD4+ cell count in subgroup analyses Feinberg J, et al. IDWeek 2015. Abstract 1075. Reproduced with permission. Wk
INTEGRASE INHIBITORS CABOTEGRAVIR orale or Long Acting GS-9883
VL < 50 c/ml by Snapshot Algorithm (%) LATTE: NRTI-Sparing Maintenance With Cabotegravir + Rilpivirine 100 80 60 Induction Phase Maintenance Phase (NRTI Sparing) Induction Regimen Maintenance Regimen 40 CAB 10 mg + 2 NRTIs* CAB 30 mg + 2 NRTIs* CAB + RPV (n = 60) CAB + RPV (n = 60) 20 CAB 60 mg + 2 NRTIs* CAB + RPV (n = 61) EFV 600 mg + 2 NRTIs* (n = 62) 0 BL 4 12 24 28 36 48 72 96 Wks 6 pts in CAB arms with PDVF at Wk 96; 4 additional pts since Wk 48 *TDF/FTC or ABC/3TC. Cabotegravir 30 mg selected for future development. 84% 75% 68% 63% Margolis D, et al. CROI 2015. Abstract 554LB.
CABOTEGRAVIR LA +RILPIVIRINE LA
OTHERS FORMULATIONS
PROJECTION
QUESTIONS AND REMARKS??